Dopamine, a neurotransmitter in the central nervous system ("CNS"), has been implicated in numerous neurological disorders. For example, it has been hypothesized that excess stimulation of dopamine receptor subtypes may be linked to schizophrenia. Additionally, it is generally recognized that either excessive or insufficient functional dopaminergic activity in the central nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.
It is generally accepted that there are at least two pharmacological subtypes of dopamine receptors (D-1 and D-2), each consisting of several molecular forms. While the physiological activities associated with the interaction with dopamine with those respective receptor subtypes are not fully understood, it is known that ligands exhibiting selectivity for activation/blockade with one or the other of the receptor subtypes produce more or less predictable, neuropharmacological results. CNS drugs exhibiting affinity for the dopamine receptors are generally classified not only by their receptor selectivity, but further by the character of their receptor interaction, i.e., by their agonist (receptor stimulating) or antagonist (receptor blocking) activity. More recently, it has been suggested that dopamine receptor ligands may further be characterized by selectivity for either presynaptic or postsynaptic receptors. As the neuropharmacological effects caused by association of selective ligands (agonist vs. antagonist) with specific receptor subtypes becomes better understood, drug researchers will be much better positioned to design CNS drugs targeting specific neurological or psychiatric disorders. Drugs with the ability to selectively block or stimulate D-1 or D-2 dopamine receptors are of significant interest in the CNS medical research community.
The present invention provides novel C.sub.2, C.sub.3, and/or C.sub.4 -substituted trans-5,6,6a, 7,8,12b-hexahydrobenzo[a]phenanthridines. They are related generally to the compounds described in co-owned U.S. Pat. No. 5,047,536, issued Sep. 10, 1991, including particularly the compound trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (dihydrexidine), a D-1 agonist which has been the subject of much study over the past several years. The biological activities of the present compounds vary significantly in their selectivity for the dopamine receptor subtypes, depending on the nature and positioning of the substituent groups. Substitution at the C.sub.2, C.sub.3, and/or C.sub.4 position on the benzophenanthridine ring system has been found to provide a means for controlling receptor affinity and concomitantly receptor selectivity. Thus, for example, 2-methyldihydrexidine has D-1 potency and efficacy comparable to dihydrexidine, while it has a five fold enhanced selectivity for the D-1 receptor. In contrast, the compound 3-methyldihydrexidine while retaining potency and efficacy as dihydrexidine, has greater D-2 potency, making it less selective but able to activate better both types of receptors. Further, data on the present substituted hexahydrobenzo[a]phenanthridines suggest that the D-2 affinity is selective for postsynaptic dopamine D-2 receptors. It is anticipated that the present ligands will offer significant therapeutic benefit over compounds exhibiting presynaptic D-2 effects because they should evoke less neural accommodation of the dopamine neurons. The postsynaptic D-2 selectivity of dihydrexidine itself and the present 2-, 3-, and/or 4-substituted dihydrexidine compounds is without antecedent in the art.
The present compounds can be administered by oral or parenteral routes of administration in amounts effective to evoke therapeutic responses in patients suffering from, for example, hypertension, Parkinson's disease, attention deficit disorder, narcolepsy, schizophrenia, other psychiatric conditions, and other diseases deriving from central nervous system dysfunction.
Additional objects, and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of preferred embodiments exemplifying the best mode of carrying out the invention.